Catechol O-methyl transferase belongs to the diverse family of S-adenosyl-l-methionine transferases. It is a target involved in the treatment of Parkinson's disease. Here we present a fragment-based screening approach to discover noncatechol derived COMT inhibitors which bind at the SAM binding pocket. We describe the identification and characterization of a series of highly ligand efficient SAM competitive bisaryl fragments (LE = 0.33-0.58). We also present the first SAM-competitive small-molecule COMT co-complex crystal structure.

Medical students perceive neurology to be a difficult subject, a phenomenon described as "neurophobia". Studies investigating student attitudes towards neurology have so far been limited by small sample sizes as a consequence of being conducted within a single medical school or region. We aimed to conduct the first national survey of the perception of neurology among UK medical students.

GPR81, which exhibits a high degree of homology with GPR109a, has been recently identified as a lactate receptor. Similar to GPR109a, the activation of GPR81 by lactate suppresses lipolysis, suggesting that GPR81 may be a potential drug target for treating dyslipidemia. In addition, the fact that GPR81 is expressed only in adipocytes, whereas GPR109a is expressed in various tissues and cells, including Langerhans cells, which are considered responsible for flushing, indicates that targeting GPR81 could lead to the development of antidyslipidemia agents with a reduced risk of this side effect. However, the pharmacological role of GPR81 remains largely unclear, mainly because of the lack of potent and selective surrogate GPR81 agonists suitable for in vivo studies. In the present study, we showed that lactate-induced suppression of lipolysis in explants of white adipose tissue (WAT) depends on the presence of GPR81. We also performed high-throughput screening (HTS) and identified four novel chemical clusters as GPR81 agonists. Chemical optimization of aminothiazole derivatives led to the discovery of a lead compound with improved potency. The compound inhibited lipolysis in differentiated 3T3-L1 adipocytes. Finally, intraperitoneal administration of this compound suppressed lipolysis in mice at doses that did not cause cutaneous flushing. This is the first description of a 50nM GPR81 selective agonist with in vivo efficacy, without the side effect, i.e., flushing. These results suggest that GPR81 is an attractive drug target for treating dyslipidemia without the risk of flushing.

Obesity is a leading cause of preventable mortality worldwide, with current strategies for treatment including life-style changes, pharmacological intervention and bariatric surgery. With pharmacological intervention showing at best modest patient benefits, new treatments are required. Modulation of anorectic gut hormones could offer the potential to elicit the required life-changing level of efficacy only currently seen with bariatric surgery, and without the cardiovascular risk associated with a number of the current marketed therapies. This review will discuss the gut hormones glucagon-like peptide-1 (GLP-1), Ghrelin and cholecystokinin (CCK) - for which more advanced non-peptide chemical matter has been discovered acting through these hormone pathways and/or their receptors.

Letter fluency deficits are commonly detected in non-demented Parkinsons disease (PD) patients but the underlying cause remains uncertain. We investigated the role of slowed processing speed and executive dysfunction. Eighteen nondemented PD participants and nineteen controls were compared on letter fluency using a fluency index (Fi); the average time to "think" of each word, a measure independent of motor speed. Video analyses produced thinking times to switch between word clusters and generate a word within a cluster. Correlational and regression analyses were undertaken with tests of processing speed and executive functioning. The PD group exhibited significantly longer fluency indices than controls across all components. Performance on tests of executive functioning explained a significant proportion of variance whereas performance in processing speed tests did not. Moreover, PD participants with an executive functioning impairment showed significantly worse switching fluency indices only compared with Controls and PD participants without executive dysfunction. PD participants with executive dysfunction exhibited a disproportionate impairment in the time taken to switch between clusters than to think of words within clusters. Executive functioning contributed to fluency performance more than processing speed. Cognitive heterogeneity and motor slowing, may mask the profile of cognitive dysfunction in neurodegenerative disease.

Autoimmune limbic encephalitis is an increasingly recognised cause of cognitive decline and confusion. The typical presentation is with subacute cognitive decline, behavioural disturbance and seizures. Magnetic resonance imaging may show characteristic changes in the medial temporal regions. The diagnosis is confirmed by identification of elevated voltage-gated potassium channel antibody (VGKC-Ab) titres. It is a highly treatable condition, often responding well to intravenous immunoglobulin or steroids. Recognition of autoimmune limbic encephalitis is sometimes delayed--usually because the diagnosis has not been considered--which can result in long-term neurological consequences.

People with one or more first degree relative affected (FDRA) by aneurysmal subarachnoid haemorrhage (aSAH) are at a higher lifetime risk of an aSAH than those without a family history. Screening may be worthwhile for people with two or more FDRA by aSAH. Little is known about the characteristics of people with a family history of aSAH who undergo screening in clinical practice.

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.